Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region.
IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European HLA-DR3 haplotypes to help localize the IgA-D susceptibility gene(s). With the knowledge that approximately 13% of HLA-DR3 homozygous individuals of North European origin are IgA-D, we examined 43 HLA-DR3 homozygous Sardinians to find that all had normal serum IgA, IgG and IgM levels. A detailed analysis of their MHC haplotypes indicated a common Sardinian HLA-DR3 haplotype TAP1A, TAP2A, HLA-DQB1*0201, -DQA1*0501, -DRB1*0301, LH1-(Z + 2), D3A-(Z + 2), C4B-0, C4A-L, G11-15, Bf-0-4, C2-a, HSP70-7.5, 9N3-(Z + 10), 82I-(Z - 2), TNFalpha-9, 62-(Z - 20), HLA-B18, -Cw5, -A30 which diverges from the common North European HLA-DR3 haplotype telomeric to the HLA-DR region. In parallel studies of five Sardinians with IgA-D, two of the 10 HLA haplotypes (20%) contained HLA-DR3, a frequency similar to that observed in the background population. One of these was the HLA-DR3- B8 North European haplotype, which occurs rarely in Sardinia. Our data favour the hypothesis that a class III region allele, present on the common North European but not on the Sardinian HLA-DR3 haplotype, confers susceptibility to IgA-D.
Cucca
F
F
Divisione Pediatrica, Ospedale S. Michele, Cagliari, Italy.
Zhu
Z B
ZB
Khanna
A
A
Cossu
F
F
Congia
M
M
Badiali
M
M
Lampis
R
R
Frau
F
F
De Virgiliis
S
S
Cao
A
A
Arnone
M
M
Piras
P
P
Campbell
R D
RD
Cooper
M D
MD
Volanakis
J E
JE
Powis
S H
SH
D004198:Disease Susceptibility; D015803:HLA-DR3 Antigen / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D017098:IgA Deficiency / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D007558:Italy / Q000453:epidemiology
D015803:HLA-DR3 Antigen